Use of lemborexant for treating insomnia

Abstract

To provide a method for treating insomnia that is effective and safe even when lemborexant is administered to a patient having moderate hepatic impairment.SOLUTION: Provided is a method comprising orally administering to a patient in need thereof a dosage form comprising lemborexant or a pharmaceutically acceptable salt thereof at a single daily dose ranging from 5 mg to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof, provided that when the patient has moderate hepatic impairment classified as Child-Pugh class B under Child-Pugh Classification, the maximum dose is 5 mg once per day of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 951,638, filed December 20, 2020, which is incorporated herein by reference.

[0002] The present disclosure relates to methods of treating insomnia. [Background technology]

[0003] Two neuropeptides, orexin-A (OX-A, a 33-amino acid peptide) and orexin-B (OX-B, a 28-amino acid peptide), expressed in neurons localized in the hypothalamus of the brain, were discovered as endogenous ligands of G protein-coupled receptors, i.e., orexin receptors, primarily present in the brain (WO 1996 / 34877, JP 10-327888, JP 10-327889, JP 11-178588, JP 10-229887, WO 2016 / 063995, and Sakurai T. et al., Cell, 1998, 92, 573-585). Orexin receptors include two subtypes: the OX1 receptor (subtype 1) and the OX2 receptor (subtype 2). OX1 preferentially binds to OX-A rather than OX-B, whereas OX2 binds to both OX-A and OX-B. Orexins have been shown to stimulate feeding in rats, suggesting that these peptides may play a physiological role as mediators in a central feedback mechanism regulating feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585).

[0004] Orexin has also been observed to regulate sleep-wake states, thus potentially treating narcolepsy, insomnia, and other sleep disorders (Chemelli RM et al., Cell, 1999, 98, 437-451). Furthermore, orexin signaling in the ventral tegmental area has been suggested to play an important role in neuroplasticity associated with drug and nicotine addiction in vivo (S.L. Borgland et al., Neuron, 2006, 49, 589-601 and C.J. Winrow et al., Neuropharmacology, 2010, 58, 185-194). Selective inhibition of OX2 has also been shown to reduce ethanol intoxication in rats (J.R. Shoblock et al., Psychopharmacology, 2010, 215:191-203). Furthermore, it has been reported that corticotropin-releasing factor (CRF), which is associated with depression and anxiety disorders, is related to orexin-induced behavior in rats, suggesting that orexin may play an important role in stress responses (T. Ida et al., Biochemical and Biophysical Research Communications, 2000, 270, 318-323).

[0005] On the other hand, lemborexant (compound name: (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide) is known to have orexin receptor antagonistic activity and can treat sleep disorders such as insomnia (T. Ida et al., Biochemical and Biophysical Research Communications, 2000, 270, 318-323).

[0006] Lemborexant, also known as E2006, has been studied in clinical trials and has been shown to possess beneficial properties, such as reduced sleep onset latency, reduced wakefulness, and / or improved sleep efficiency (see, e.g., U.S. Pat. No. 8,268,848 B2 and PCT International Application No. PCT / US2019 / 039333, both of which are incorporated herein by reference in their entireties). Summary of the Invention [Problem to be solved by the invention]

[0007] Because CYP3A-mediated metabolism is the primary clearance pathway for lemborexant, subjects with hepatic impairment may have difficulty metabolizing lemborexant, which may affect the PK of lemborexant and lead to its contraindication. However, there is a need for methods of treating patients with moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification. The objective of the present disclosure is to provide a method of treating insomnia that is effective and safe when administered to patients with moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification. [Means for solving the problem]

[0008] In some embodiments, disclosed herein is a method of treating insomnia, comprising orally administering to a patient in need thereof a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof at a single daily dose ranging from 5 mg to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof, provided that when the patient has moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof. In some embodiments, the patient does not have severe hepatic impairment classified as Child-Pugh Class C according to the Child-Pugh classification.

[0009] In some embodiments, disclosed herein is a method of treating insomnia, comprising orally administering to a patient in need thereof a dosage form comprising lemborexant or a pharmaceutically acceptable salt thereof, wherein a 5 mg dose of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof is administered orally to the patient not more than once per night, immediately prior to going to bed with at least 7 hours remaining until the patient's planned wake-up time, and this dose may be increased to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof based on clinical response and tolerability, with the proviso that when the patient has moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof. In some embodiments, the patient does not have severe hepatic impairment classified as Child-Pugh Class C according to the Child-Pugh classification.

[0010] In some embodiments, disclosed herein is a method for treating insomnia, comprising orally administering a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to patients with moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, wherein the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, disclosed herein is a method for treating insomnia in a patient with moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, comprising orally administering once daily a dosage form comprising 5 mg of lemborexant or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, disclosed herein is a method of treating insomnia in a patient, comprising the steps of determining the patient's level of hepatic impairment based on the Child-Pugh classification, and orally administering to the patient a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof, wherein a 5 mg dose of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof is administered orally to the patient no more than once per night, immediately prior to going to bed with at least 7 hours remaining until planned wake-up time; when the patient has no hepatic impairment or has mild hepatic impairment classified as Child-Pugh Class A based on the Child-Pugh classification, this dose may be increased based on clinical response and tolerability up to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof; and when the patient has moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0013] According to the present disclosure, insomnia treatment can be effective and safe for patients with moderate hepatic dysfunction classified as Child-Pugh class B based on the Child-Pugh classification. [Brief explanation of the drawings]

[0014] [Figure 1] Mean (±SD) plasma lemborexant concentration-time profiles over 12 hours following administration of 10 mg lemborexant to healthy control subjects with normal hepatic function, patients with mild hepatic impairment, and patients with moderate hepatic impairment. [Figure 2] Mean (±SD) plasma lemborexant concentration-time profiles over 312 hours following administration of 10 mg lemborexant to healthy control subjects with normal hepatic function, patients with mild hepatic impairment, and patients with moderate hepatic impairment. [Figure 3] The geometric mean ratios (90% confidence intervals) for patients with mild or moderate hepatic impairment to healthy control subjects with normal liver function are shown. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein, the following definitions shall apply unless otherwise indicated.

[0016] As used herein, the term "a" refers to one or more.

[0017] As used herein, the term "lemborexant" means a compound having the structure: [ka] which is also known as (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide or (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide. Lemborexant or a pharmaceutically acceptable salt thereof can be prepared, for example, by the methods described in WO 2012 / 039371 and WO 2013 / 123240.

[0018] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects. Examples of such salts include, but are not limited to, (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like, and (b) salts formed from elemental anions such as chlorine, bromine, and iodine. See, for example, Haynes, et al., J. Pharm. Sci., 2005, 94, 10 and Berge, et al., J. Pharm. Sci., 1977, 66, 1, which are incorporated herein by reference.

[0019] In some embodiments, lemborexant or a pharmaceutically acceptable salt thereof is administered in a solid dosage form, such as, for example, capsules, granules, lozenges, pellets, pills, powders, suspensions, and tablets.

[0020] In some embodiments, the dosage form further comprises at least one additional pharmaceutically acceptable ingredient, which in some embodiments is selected from a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, and a pharmaceutically acceptable excipient.

[0021] Dosage forms disclosed herein are orally administered to patients with insomnia and contain a dose of lemborexant in the range of 5 mg to 10 mg, or an equivalent dose of a pharmaceutically acceptable salt of lemborexant. In some embodiments, the dosage form contains 5 mg of lemborexant. In some embodiments, the dosage form contains a pharmaceutically acceptable salt of lemborexant at a dose equivalent to 5 mg of lemborexant. In some embodiments, the dosage form contains 10 mg of lemborexant. In some embodiments, the dosage form contains a pharmaceutically acceptable salt of lemborexant at a dose equivalent to 10 mg of lemborexant.

[0022] As used herein, the term "pharmaceutically acceptable" means the carrier, diluent, excipient or vehicle is compatible with the other ingredients of the composition and is non-toxic and non-toxic to the subject.

[0023] As used herein, the term "pharmaceutically acceptable excipient" refers to an inactive ingredient used as a vehicle (e.g., water, capsule shells, etc.), diluent, or component to constitute a dosage form or pharmaceutical composition containing a drug, such as a therapeutic agent. The term also encompasses inactive ingredients that impart cohesive (e.g., binders), disintegrant (e.g., disintegrants), lubricant (e.g., lubricants), and / or other functions (e.g., solvents, surfactants, etc.) to the composition.

[0024] As used herein, the term "patient" refers to an animal subject, such as a mammalian subject, and for example, a human. As used herein, a subject can be of any age. In some embodiments, a subject can be 18 years of age or older.

[0025] As used herein, the terms "treatment" and "treating" refer to an approach for achieving beneficial or desired results, including but not limited to, a therapeutic benefit and / or a prophylactic benefit.

[0026] As used herein, the term "insomnia" means a disorder defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013; "DSM-V") with the following diagnostic criteria: A. The subject's primary complaint is dissatisfaction with the quantity or quality of sleep, accompanied by one (or more) of the following symptoms: 1. Difficulty falling asleep (in children, this may manifest as difficulty falling asleep without caregiver assistance). 2. Difficulty maintaining sleep, characterized by frequent awakenings or problems falling asleep again after awakenings (in children, this may manifest as difficulty falling asleep again without caregiver assistance). 3. Early morning awakening with no ability to fall back asleep. B. The sleep disturbance causes clinically significant distress or interferes with social, work, school, academic, behavioral, or other important aspects of life. C. Sleep difficulties occur at least 3 nights per week. D. Sleep difficulties have persisted for at least 3 months. E. Difficulty sleeping despite adequate sleep opportunities. F. The insomnia is not better explained by, and does not occur exclusively during, another sleep-wake disorder (e.g., narcolepsy, breathing-related sleep disorder, circadian rhythm sleep-wake disorder, parasomnia). G. The insomnia is not caused by the physiological effects of a substance (e.g., a drug of abuse, a medication being taken). H. Comorbid psychiatric disorders and conditions do not adequately explain the primary complaint of insomnia.

[0027] The term "insomnia" also refers to a sleep disorder characterized by symptoms including, but not limited to, difficulty falling asleep, difficulty staying asleep, repeated awakenings, and / or waking up too early. The term also encompasses daytime symptoms such as drowsiness, anxiety, poor concentration, poor memory, and irritability. Types of insomnia suitable for treatment with lemborexant or a pharmaceutically acceptable salt thereof include short-term insomnia and chronic insomnia.

[0028] As used herein, "treating insomnia" refers to achieving a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit.

[0029] As used herein, the term "C max " indicates the highest concentration in plasma.

[0030] As used herein, the term "AUC (0-inf) " indicates the area under the plasma concentration-time curve from immediately after administration of the drug (time 0) to infinity.

[0031] Herein, the "Child-Pugh Classification" score is used as a marker of the degree of liver dysfunction, which is evaluated according to the criteria in Table 1.

[0032] [Table 1]

[0033] In some embodiments, disclosed herein is a method of treating insomnia, comprising orally administering to a patient in need thereof a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof at a single daily dose ranging from 5 mg to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof, provided that when the patient has moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof. In some embodiments, the patient does not have severe hepatic impairment classified as Child-Pugh Class C according to the Child-Pugh classification.

[0034] In some embodiments, disclosed herein is a method of treating insomnia, comprising orally administering to a patient in need thereof a dosage form comprising lemborexant or a pharmaceutically acceptable salt thereof, wherein a 5 mg dose of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof is administered orally to the patient not more than once per night, immediately prior to going to bed with at least 7 hours remaining until the patient's planned wake-up time, and this dose may be increased to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof based on clinical response and tolerability, with the proviso that when the patient has moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof. In some embodiments, the patient does not have severe hepatic impairment classified as Child-Pugh Class C according to the Child-Pugh classification.

[0035] In some embodiments, disclosed herein is a method for treating insomnia, comprising orally administering a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to a patient with moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, wherein the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, disclosed herein is a method for treating insomnia in a patient with moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, comprising orally administering once daily a dosage form comprising 5 mg of lemborexant or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, disclosed herein is a method of treating insomnia in a patient, comprising the steps of determining the patient's level of hepatic impairment based on the Child-Pugh classification, and orally administering to the patient a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof, wherein a 5 mg dose of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof is administered orally to the patient no more than once per night, immediately prior to going to bed with at least 7 hours remaining until planned wake-up time; when the patient has no hepatic impairment or has mild hepatic impairment classified as Child-Pugh Class A based on the Child-Pugh classification, this dose may be increased based on clinical response and tolerability up to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof; and when the patient has moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0038] Non-limiting embodiments of the present disclosure include the following.

[0039] Embodiment 1: A method of treating insomnia, comprising: Oral administration of a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to a patient in need thereof at a single daily dose ranging from 5 mg to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof provided that when the patient has moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0040] Embodiment 2: A method of treating insomnia, comprising: Oral administration of a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to a patient in need thereof. Including, A 5 mg dose of lemborexant, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered orally to a patient not more than once nightly, immediately prior to going to bed with at least 7 hours remaining until the intended wake-up time; This dose may be increased up to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof based on clinical response and tolerability, except that when patients have moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0041] Embodiment 3: The method of embodiment 1 or 2, wherein the patient does not have severe hepatic dysfunction classified as Child-Pugh class C based on the Child-Pugh classification.

[0042] Embodiment 4: A method of treating insomnia, comprising: Oral administration of a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to patients with moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification. wherein the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0043] Embodiment 5: A method of treating insomnia in a patient with moderate hepatic impairment classified as Child-Pugh Class B according to the Child-Pugh classification, comprising: A dosage form containing 5 mg of lemborexant or an equivalent amount of its pharmaceutically acceptable salt is to be administered orally once daily. A method comprising:

[0044] Embodiment 6: A method of treating insomnia, comprising: determining, in the patient, the patient's level of liver dysfunction based on the Child-Pugh classification; and orally administering to the patient a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof. Including, A 5 mg dose of lemborexant, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered orally to a patient not more than once nightly, immediately prior to going to bed with at least 7 hours remaining until the intended wake-up time; When patients have no hepatic impairment or mild hepatic impairment classified as Child-Pugh Class A based on the Child-Pugh classification, this dose may be increased to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof based on clinical response and tolerability. When patients have moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof. [Example]

[0045] The following examples illustrate various aspects of the present disclosure and should not be construed as limiting the scope of the disclosure.

[0046] A multicenter, single-dose, open-label, parallel-group study was conducted in subjects with mild or moderate hepatic impairment and matched healthy subjects (in terms of age [±10 years], sex, and body mass index [BMI, ±20%]) as controls.

[0047] The primary objective of this study was to evaluate the effect of mild and moderate hepatic impairment on the PK of lemborexant after single-dose administration.

[0048] Secondary objectives of this study were to determine the effect of hepatic impairment on the PK of lemborexant metabolites M4, M9, and M10; to determine the relationship between PK parameters of lemborexant and its metabolites and Child-Pugh score, serum albumin, total bilirubin, and PT; and to evaluate the safety and tolerability of single-dose lemborexant in subjects with mild or moderate hepatic impairment and healthy control subjects.

[0049] Research Phase The study consisted of two phases: pretreatment and treatment.

[0050] The pretreatment phase included two study periods: screening and baseline (Day -1). Subjects were admitted to the clinic on Day -1, remained confined to the clinic until Day 8, and then returned to the clinic as outpatients for additional PK sampling until Day 14. If subjects discontinued early, Child-Pugh class A and B subjects (Cohorts A and B) and matched healthy controls (Cohort C) were allowed to recruit.

[0051] The treatment phase consisted of one 14-day study period.

[0052] On Day 1, subjects received a single oral 10 mg dose of lemborexant in approximately 240 mL of water in the morning after an overnight fast. Food was prohibited for at least 4 hours after administration. Water was available ad libitum, except for 1 hour before and after drug administration.

[0053] Blood samples for PK assessment were collected at predetermined intervals up to 312 hours after dose administration. In addition, blood samples for lemborexant plasma protein binding assessment were collected from each subject at two time points: approximately 1 hour and 24 hours after dosing. Subjects were discharged on study day 14. Study termination occurred on the last day of the last subject's study visit.

[0054] subject Subjects were eligible to participate in the study if they met all of the inclusion criteria and none of the exclusion criteria listed below: 1. Male or female subjects, aged 18-79 years at the time of informed consent. 2. BMI at screening is 18-40 kg / m 2 . 3. Non-smokers or smokers who smoke less than 20 cigarettes per day. 4. For Cohorts A and B: Child-Pugh classification A or B, respectively (see Table 1), and stable (no change in disease status for at least 60 days prior to study screening) liver dysfunction confirmed by medical history and physical examination. 5. For Cohort C: Healthy control subjects who match subjects with liver dysfunction in terms of age (±10 years), sex, and BMI (±20%) as determined by the absence of clinically significant deviations from normal in medical history, physical examination, ECG, and clinical laboratory measurements.

[0055] All subjects were prohibited from consuming foods, beverages, or supplements (e.g., St. John's wort) that affect CYP3A enzymes or transporters (e.g., foods containing grapefruit, mustard greens).

[0056] A total of 28 subjects were enrolled, and 24 subjects passed screening, received the dose, and completed the study. All 24 subjects who enrolled and received the dose (8 subjects per cohort) were included in the safety and PK analysis set.

[0057] Cohort A - Child-Pugh Class A: There were 2 female and 6 male subjects. The mean age was 57.0 years.

[0058] Cohort B - Child-Pugh Class B: There were 2 female and 6 male subjects. The mean age was 61.4 years.

[0059] Cohort C - Healthy Control Subjects: 3 female and 5 male subjects. Mean age was 56.8 years.

[0060] evaluation Pharmacokinetics Blood samples (4 mL each) for PK assessment of lemborexant and its metabolites (M4, M9, and M10) were collected pre-dose (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 216, 264, and 312 hours post-dose. In addition, blood samples (12 mL per time point) for protein binding of lemborexant and its metabolites (M4, M9, and M10) were collected at 1 hour and 24 hours post-dose corresponding to the PK sampling at these time points.

[0061] Total mean plasma concentrations of lemborexant and lemborexant metabolites (M4, M9, and M10) were measured by a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Concentrations of unbound lemborexant, M4, M9, and M10 were also measured using a similar validated LC-MS / MS method followed by equilibrium dialysis.

[0062] Safety evaluation Safety was assessed by monitoring and recording treatment-emergent adverse events (TEAEs), ECG, vital signs, weight, physical examination and laboratory values ​​(urinalysis, hematology and blood chemistry).

[0063] result In patients with mild hepatic impairment, lemborexant C was significantly lower than in patients with normal liver function. max and AUC (0-inf) The effects of moderate hepatic impairment on lemborexant PK were similar. max and AUC (0-inf) The values ​​were increased by 22% and 54%, respectively, in subjects with moderate hepatic impairment compared to healthy subjects (Figure 3). The systemic clearance of lemborexant was decreased by 20% and 35%, respectively, in subjects with mild and moderate hepatic impairment compared to healthy subjects. Thus, administration of 10 mg lemborexant to subjects with hepatic impairment increased lemborexant exposure compared to administration of 10 mg lemborexant to healthy subjects.

[0064] [Table 2]

[0065] Lemborexant exposure (geometric mean C max , AUC (0-t) and AUC (0-inf) The mean mean hepatic function (based on the mean mean hepatic function) was higher in subjects with mild or moderate hepatic impairment compared with healthy control subjects. max Median values ​​were comparable across cohorts, ranging from 1.00 to 1.25 hours. Geometric mean CL / F decreased with increasing hepatic impairment (17.6 L / h for subjects with mild hepatic impairment and 14.4 L / h for subjects with moderate hepatic impairment) and was lower than that observed in healthy control subjects (22.1 L / h). A longer geometric mean half-life was observed in subjects with hepatic impairment (73.7 hours for subjects with mild hepatic impairment and 105 hours for subjects with moderate hepatic impairment) compared with healthy control subjects (67.0 hours). Geometric mean lemborexant f in subjects with mild and moderate hepatic impairment u The AUC values ​​were 0.0630 and 0.0650, respectively, which were comparable to those of healthy control subjects (0.0597). u The tendency for AUC to be higher and CLu / F to be lower is (0-inf) and CL / F were consistent with the observations.

[0066] [Table 3]

[0067] Lemborexant C max and AUC (0-inf) were 58% and 25% higher, respectively, in subjects with mild hepatic impairment and 22% and 54% higher, respectively, in subjects with moderate hepatic impairment compared to healthy control subjects.

[0068] Lemborexant was extensively metabolized to the metabolites M4, M9, and M10. Hepatic impairment had no effect on the metabolite-to-parent exposure ratios for M4, M9, and M10. Furthermore, the t 1 / 2 was unchanged in subjects with mild liver dysfunction compared with healthy subjects, and showed a slight increase of 1.5 to 2.1 times in subjects with moderate liver dysfunction.

[0069] [Table 4]

[0070] The geometric mean C for each of the lemborexant metabolites (M4, M9, and M10) max was lower in subjects with mild or moderate hepatic impairment compared with healthy control subjects, and no clear differences were observed in the median tmax of each metabolite between cohorts. In general, the exposures based on AUC for M4, M9, and M10 were comparable between cohorts, and no consistent trends were observed in changes in metabolite exposure with hepatic impairment. In subjects with mild or moderate hepatic impairment, lemborexant exposure (AUC (0-inf) ) is higher, reflecting the AUC (0-inf) The geometric mean metabolite-to-parent ratio (MPR) of was decreased with liver dysfunction compared with healthy control subjects.

[0071] The relationships between PK parameters of lemborexant and its metabolites and Child-Pugh score, serum albumin, total bilirubin, MELD score, and PT were explored using scatter plots and linear regression. The effects of mild and moderate hepatic impairment on lemborexant were small and comparable. No consistent evidence of a relationship between lemborexant PK and hepatic function was found.

[0072] Safety was comparable between mild, moderate, and healthy subjects. No SAEs were reported. A total of 20 (83.3%) subjects experienced TEAEs during the study: 7 (87.5%), 6 (75.0%), and 7 (87.5%) subjects in Class A, Class B, and healthy controls, respectively. All TEAEs during the study were mild in severity, and none led to subject discontinuation. TEAEs were not associated with clinically significant abnormalities in laboratory values, ECG, vital signs, or physical examination. No TEAEs were potentially related to cataplexy.

Claims

1. 1. A method for treating insomnia, comprising: Orally administering a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to a patient in need thereof in a single daily dose ranging from 5 mg to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof. wherein when the patient has moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

2. 1. A method for treating insomnia, comprising: Oral administration of a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to a patient in need thereof. Including, a 5 mg dose of lemborexant, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered orally to a patient not more than once per night immediately prior to going to bed with at least 7 hours remaining until planned awakening time; The dose may be increased based on clinical response and tolerability up to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof, provided that when the patient has moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily or an equivalent dose of a pharmaceutically acceptable salt thereof.

3. 3. The method of claim 1 or 2, wherein the patient does not have severe hepatic dysfunction classified as Child-Pugh class C based on the Child-Pugh classification.

4. 1. A method for treating insomnia, comprising: Oral administration of a dosage form containing lemborexant or a pharmaceutically acceptable salt thereof to patients with moderate hepatic impairment classified as Child-Pugh Class B based on the Child-Pugh classification. wherein the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

5. 1. A method for treating insomnia in a patient with moderate hepatic dysfunction classified as Child-Pugh Class B based on the Child-Pugh classification, comprising: A dosage form containing 5 mg of lemborexant or an equivalent amount of a pharmaceutically acceptable salt thereof is orally administered once daily. A method comprising:

6. 1. A method for treating insomnia, comprising: determining in the patient the patient's level of liver dysfunction based on the Child-Pugh classification; and orally administering to said patient a dosage form comprising lemborexant or a pharmaceutically acceptable salt thereof. Including, a 5 mg dose of lemborexant, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered orally to the patient not more than once per night, immediately prior to going to bed with at least 7 hours remaining until planned awakening time; When the patient has no hepatic impairment or mild hepatic impairment classified as Child-Pugh Class A based on the Child-Pugh classification, the dose may be increased to 10 mg of lemborexant or an equivalent dose of a pharmaceutically acceptable salt thereof based on clinical response and tolerability; When the patient has moderate hepatic impairment classified as Child-Pugh class B based on the Child-Pugh classification, the maximum dose is 5 mg of lemborexant once daily, or an equivalent dose of a pharmaceutically acceptable salt thereof.

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